The combination of aztreonam and avibactam (ATM-AVI) has shown promising results in two phase 3 studies in the fight against antibiotic-resistant carbapenem-resistant enterobacteriaceae (CRE), which are widely considered to be among the most dangerous drug-resistant bacteria in the world. Aztreonam is an antibiotic, but it falls prey to beta-lactamases, which are released by the carbapenem-resistant enterobacteriaceae. Avibactam targets the beta-lactamases, effectively protecting the aztreonam so that it can do its job. CRE bacteria can cause infections in almost any body part, creating a range of problems including urinary tract infections, bloodstream infections, ventilator-associated pneumonia and intra-abdominal abscesses. Treating CRE infections is extremely difficult. These bacteria are resistant to a wide range of drugs and a new arsenal of treatments is needed. Infection with CRE can result in death, and the rates of CRE infections are on the rise in EU countries.
Thanks to the Innovative Medicines Initiative’s COMBACTE-CARE project and building on the results of a Phase 2 study called REJUVENATE, a Phase 3 study called REVISIT was conducted by Pfizer which produced data supporting the ATM-AVI combination approach. The REVISIT data suggested that ATM-AVI was effective in treating serious bacterial infections due to Gram-negative bacteria, including metallo-β-lactamase (MBL)-producing multidrug-resistant pathogens for which there are limited or no treatment options. It was also tolerated well by patients, with no new safety concerns arising.
“The REVISIT study was made possible by funding from the EU’s IMI programme and its success is thanks to collaboration across academia and industry to design and implement the REVISIT study in clinical sites and hospitals from the COMBACTE CLIN-Net network,” said Rienk Pypstra, project coordinator of the COMBACTE-CARE project and VP of Clinical Development for the Anti-Infective Portfolio at Pfizer.
“Data from the REVISIT study will enable the ATM-AVI combination to be formally submitted for marketing authorisation to health regulators across the globe. If approved, ATM-AVI would be an important treatment option for patients with life-threatening bacterial infections that are resistant to almost all currently available antibiotics.”
The REVISIT study examined patients presenting with complicated intra-abdominal infections, hospital-acquired pneumonia and ventilator-associated pneumonia. In total 165 global sites were activated for enrolment in the trial, 75 of which were from the COMBACTE Clin-net network. 422 patients from all over the world were randomly assigned to one treatment or the other, and 201 of these patients came from the COMBACTE Clin-net network.
“I am excited that the European clinical and laboratory trial network that we started to build in 2013, as part of the IMI-funded New Drugs for Bad Bugs (ND4BB) programme COMBACTE-Net, could make such an important contribution to the REVISIT study, delivering 48% of all enrolled patients,” said Prof. Marc Bonten, Chief Executive Officer of the European Clinical Research Alliance on Infectious Diseases (Ecraid), who is also the academic coordinator of COMBACTE-CARE.
“The networks will now continue as part of the European Clinical Research Alliance on Infectious Diseases (Ecraid) dedicated to enhance the efficiency of clinical trials in infectious diseases and to lessen the burden of antibiotic resistance in Europe.”
The combination of ATM-AVI and in some cases metronidazole was compared to an alternative treatment with the antibiotic meropenem (with colistin when needed) and the ATM-AVI treatment generally showed better results.
One key result showed that no patient who received the combination of ATM-AVI experienced serious adverse effects related to the treatment. Similar results emerged from a second phase 3 study called ASSEMBLE, which was conducted outside COMBACTE-CARE. The full results of this study, together with the results of ASSEMBLE, will be published in a peer-reviewed scientific journal and the next steps will be to submit a marketing authorisation application to regulators such as the European Medicines Agency in Europe.
Antibiotic-resistant bacteria cause approximately 33 000 deaths in the EU, while the annual treatment and social costs have been estimated at approximately 1.5 billion euros. An estimated 1.27 million deaths globally were caused by bacterial antibiotic resistance in 2019 alone. Continued research is needed in this area to identify solutions, as antibiotic resistance is on the rise.
COMBACTE-CARE is supported by the Innovative Medicines Initiative, a partnership between the European Union and the European pharmaceutical industry. It is also part of the IMI New Drugs for Bad Bugs programme.